Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking

Etude de composés terpéniques vasorelaxants de Croton zambesicus Müell. Arg

Les feuilles de Croton zambesicus (Euphorbiaceae), un arbre originaire d'Afrique tropicale et sub-tropicale, sont utilisées en médecine traditionnelle béninoise sous forme de décocté aqueux pour traiter les infections microbiennes, la fièvre et l'hypertension. Ce travail a été consacré à l'étude des propriétés vasorelaxantes et antihypertensives de différents extraits de cette plante ainsi que de ces principes actifs. Dans un premier temps nous avons analysé les effets in vivo et in vitro d'un extrait aqueux des feuilles de C. zambesicus afin de rechercher des fondements scientifiques à son utilisation en médecine traditionnelle. N'ayant pas observé un effet même à doses élevées nous avons décidé d'évaluer l'activité d'extraits plus apolaires car plusieurs espèces appartenant au genre Croton sont connues pour contenir des diterpènes, composés lipophiles à 20 atomes de carbones. La fraction apolaire de l'extrait aqueux frais a montré la meilleure activité vasorelaxante in vitro sur aortes de rat contractées avec une solution dépolarisante riche en KCl (100mM). In vivo son administration orale (80 mg d'extrait/Kg/jour pendant 1 semaine) a induit une diminution significative de la tension artérielle sans signes de toxicité. L'analyse de la composition de cet extrait par chromatographie gazeuse a confirmé la présence de diterpènes appartenant aux familles des trachylobanes et des pimaranes. Pour certains de ces composés nous avons mis au point des nouveaux protocoles d'extraction à l'aide de techniques de chromatographie préparative tels que la CPC, la MPLC et la OPLC. Une fois les composés isolés en quantités suffisantes nous avons évalué leur activité vasorelaxante que nous avons comparée à celle de certains dérivés (hémi) synthétiques. Ce qui nous a permis non seulement de montrer pour la première fois l'activité vasorelaxante des trachylobanes mais aussi de proposer des relations structure-effet vasorelaxant pouvant servir de base pour la synthèse de nouveaux diterpènes actifs. Parmi les différents extraits analysés nous avons également étudié la composition de l'huile essentielle pour laquelle nous avons observé une très bonne activité vasorelaxante due en autre aux diterpènes qu'elle contientThèse de doctorat en sciences pharmaceutiques (FARM 3)--UCL, 200

Vasorelaxant activity of essential oils from Croton zambesicus and some of their constituents.

In this study, we determined the vasorelaxant activity of essential oils of different samples of CROTON ZAMBESICUS collected in the same area in Benin at different periods and analysed their compositions by GC-FID and GC-MS. 68 compounds were identified among which 20 have not been described previously in this plant's essential oils. We observed quantitative differences among essential oils but all possess significant vasorelaxant activity on intact rat aortae contracted by KCl (IC (50) 5.6-11.8 µg/mL). This activity may, at least in part, be explained by the presence of vasorelaxant diterpenes such as ENT-18-hydroxy-trachyloban-3-one, isopimara-7,15-dien-3β-ol, and ENT-18-hydroxy-isopimar-7,15-dien-3β-ol, previously isolated from the dichloromethane extract of the leaves, but also to linalool (IC (50) 43.4 µg/mL) and particularly to caryophyllene oxide (IC (50) 2.5 µg/mL)

Effects of leaf extracts from Croton zambesicus Müell. Arg. on hemostasis

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf decoction of Croton zambesicus Müell. Arg. (Euphorbiaceae; syn. Croton amabilis Müell. Arg., Croton gratissimus Burch) is traditionally used in Benin to treat hypertension. AIM OF THE STUDY: As hypertension and thromboembolism are often associated in several cardiovascular diseases, we studied the potential effects of leaf extracts from Croton zambesicus on hemostasis. MATERIALS AND METHODS: We prepared the dichloromethane and aqueous extracts from the air-dried leaves of Croton zambesicus and separated the aqueous extract in its aqueous and dichloromethane fractions. The potential effects of these four extracts/fractions were investigated on red blood cells integrity using spectrophotometric lysis assays, on primary hemostasis using platelet aggregation studies and on secondary hemostasis using calibrated automated thrombin generation assays and coagulation factors inhibition tests. RESULTS: In the in vitro testing, we found that none of the tested extracts/fractions exhibit hemolytic or antiplatelet activity. However, they display a moderate but significant anticoagulant activity which would be mediated through the direct inhibition of thrombin, FXa and TF/FVIIa. The active anticoagulant compound(s) seem to be mainly in the aqueous extract and especially in its aqueous fraction. CONCLUSIONS: This experimental work reported for the first time the anticoagulant effect of leaf extracts from Croton zambesicus. These findings are of particular interest as the leaves from Croton zambesicus are commonly used in infusion by local population and may provide a new natural source for the development of original anticoagulant agents. Furthermore, this activity, associated with the vasorelaxant properties of some of its diterpenes may prove to be interesting for the prevention of cardiovascular diseases in traditional medicine

Vascular activity of a natural diterpene isolated from Croton zambesicus and of a structurally similar synthetic trachylobane.

The aim of this study was to determine the vasorelaxant activity of a natural diterpene extracted from Croton zambesicus, ent-18-hydroxy-trachyloban-3-one (DT6), and a synthetic diterpene of similar structure, ent-trachyloban-14,15-dione (DT10) in rat aorta. DT6 and DT10 inhibited aorta contraction in a concentration-dependent manner. Both were more potent inhibitors of KCl-evoked contraction than noradrenaline-evoked contraction. Nitric oxide (NO) synthase inhibition did not significantly affect DT6 effect whereas it significantly decreased DT10 inhibitory potency. In fura-2 loaded aorta rings, DT10 simultaneously inhibited KCl-evoked contraction and cytosolic calcium increase in a concentration-dependent manner. Furthermore, DT10 significantly inhibited calcium channel current recorded by the patch-clamp technique in human neuroblastoma cells SH-SY5Y. However, despite potentiation of 8-bromo-cGMP-response, DT6 and DT10 as verapamil depressed acetylcholine-evoked relaxation, DT6 being the most potent, while only DT6 and DT10 depressed SNAP-evoked relaxation. In conclusion, these data suggest that vasorelaxant activity of diterpenes (DT) is associated with the blockade of L-type voltage-operated calcium channels. Inhibition of NO-dependent relaxation by DT could be related to a decrease in NO availability

Vasorelaxant activity of diterpenes from Croton zambesicus and synthetic trachylobanes and their structure-activity relationships

The diterpenes previously isolated from the leaves of Croton zambesicus were tested to evaluate their vasorelaxant activity on the Wistar rat aorta. Their vasorelaxant effect was compared to a series of synthetic trachylobanes and related polycyclic compounds on KCl- or noradrenaline-induced contractions in order to evaluate structure-activity relationships. We demonstrate the vasorelaxant properties of some pure trachylobane diterpenes at low concentration (IC50 < 10 microM) on KCl-induced contractions, but none have a significant effect in noradrenaline-induced contractions. Comparing structures and activity we observed that a C-14 carbonyl group associated with a C-15 hydroxy or ketone function or a C-3 carbonyl associated with a hydroxymethyl group plays an important role in the vasorelaxant activity of trachylobane diterpenes. We also observed that the absolute configuration or the cleavage of the C13-C16 cyclopropane bond does not have a marked effect on the activity. The cytotoxicity of all of these compounds has also been evaluated on HeLa cells in order to verify that the vasorelaxant activity was not correlated with general cytotoxicity

Anti-inflammatory compounds from leaves and root bark of Alchornea cordifolia (Schumach. & Thonn.) Müll. Arg.

Alchornea cordifolia is one of the most widely-used plants in traditional medicine throughout Africa, principally for inflammatory, antimicrobial and parasitic diseases. In continuation of our investigations on its anti-inflammatory activity, we fractionated the leaf and root bark extracts and isolated six compounds which exhibited significant topical anti-inflammatory activity in the mouse ear oedema model using croton oil at a dose of 90 microg/cm2. Daucosterol (2), acetyl aleuritolic acid (4), N1,N2-diisopentenyl guanidine (5) and N1,N2,N3-triisopentenyl guanidine (6) were shown to be more active than indomethacin, while beta-sitosterol (1) and di(2-ethylhexyl) phthalate (3) were less effective. This is the first report on the presence of compounds 1, 2, 3 and 4 in this plant and of the anti-inflammatory activity of 3, 5 and 6. These compounds may account, at least in part, for the use of A. cordifolia in folk medicine to treat inflammation